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In a review of previous, current and future modalities for MRSA, the panelists weigh the pros and cons of various medications, and discuss the importance of differentiating hospital-acquired strains from community-acquired strains of MRSA.
Dr. Armstrong: While vancomycin is commonly used for MRSA infections and perceived by most as a “big gun” antibiotic, it has its problems, doesn’t it?
Dr. Joseph: We’ve held vancomycin out to be the gold standard drug for methicillin resistant Staph because it’s been available for over 40 years. With the exception of trimethoprim-sulfamethoxazole or one of the tetracyclines which have never really been adequately studied in methicillin resistant Staph, vancomycin would have been the only drug out there. I think we have to start rethinking that a little bit.
Vancomycin is not an ideal drug. We stated some of the problems with it in the previous supplement.3 A year ago, we had Dr. Lipsky’s study in which he found therapy with linezolid for diabetic foot infections superior to “standard therapy” (an aminopenicillin-lactamase inhibitor combination) for infected ulcers.5
However, at the recent meeting of the Infectious Diseases Society of America, there were two posters on complicated skin and skin structure infections. Weigelt compared vancomycin to linezolid in 1,200 patients with complicated skin and skin structure infections.6 Sharpe compared vancomycin to linezolid in the treatment of complicated skin and skin structure infections in 60 patients.7 Both studies, which were powered to demonstrate superiority and not equivalence, found that linezolid was a superior drug to vancomycin.6,7
|  | | “Linezolid recently became only the second drug that the FDA has
specifically approved for diabetic foot infections.”
— Dr. Lipsky
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I think we’re looking at a shift. The currently available drugs and the newer ones that are going to be coming out on the market appear to be superior to vancomycin. We are going to have to rethink the role of not only linezolid but the other new drugs that are in development as well. We may have to start thinking a lot differently about how we approach methicillin resistant Staph.
Dr. Lipsky: I think Dr. Joseph raises a good point. If you’re faced with treating a MRSA infection and vancomycin is your only drug, that’s what you use. But we’ve known for decades that vancomycin has problems in terms of its pharmacology, its toxicity and its efficacy. It fell out of favor soon after it was developed, largely because the old preparations were relatively toxic.3 It has been resurrected in the last 10 to 20 years because of the problem of MRSA. While modern preparations of vancomycin are less toxic, levels of the drug still need to be monitored to ensure its safety and efficacy.9-14 It is also only available for parenteral use.
The pharmaceutical industry responded to the increased prevalence and importance of MRSA infections, and several companies have developed new agents. The first new antibiotic on the market active against MRSA was quinupristin-dalfopristin, which had a very brief flare and is largely dying out. The relatively high rate of toxicities, difficulties in administering the drug and the availability of only a parenteral preparation have resulted in the drug being infrequently used.
The next new drug for treating MRSA (and other gram-positive pathogens) was linezolid, which is available parenterally and orally.15-23 This dual formulation is a major advantage. The drug also has virtually 100 percent bioavailability so you can get equivalent serum levels whether you take it parenterally or orally. Linezolid has been used in a large number of studies, including for skin and skin structure infections and, specifically, for diabetic foot infections. It recently became only the second drug that the FDA has specifically approved for the indication of diabetic foot infections. The other drug was trovafloxacin, which is no longer used. Currently, linezolid is the only drug with a specific indication due to the large study that compared linezolid to aminopenicillin-beta lactamase inhibitor therapy.5
Just recently, the FDA approved daptomycin, another new agent for treating skin and soft tissue infections.24-26 It also represents a new class of lipopeptide antibiotics. One major advantage for daptomycin is it’s a highly bactericidal agent. For those few infections for which a bactericidal agent is preferred over a bacteriostatic agent, one might prefer daptomycin. It can also be given once daily rather than twice daily, a particular advantage of outpatient parenteral therapy. Unfortunately, there is no oral preparation. To date, the drug appears to be quite safe, but has been associated with elevated muscle enzymes.27
|  | | Here is a MRSA infection that was acquired in the community following a gunshot wound to the lateral foot.
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Dr. Armstrong: I believe there are several other drugs that are in the pipeline for treating infections caused by resistant gram-positive organisms. What about oritavancin, tigecycline and dalbavancin?
Dr. Lipsky: Yes, oritavancin and tigecycline are now in development.28 Tigecycline can be given once daily and has a broader spectrum of antimicrobial activity than some of the previous drugs we mentioned, which are largely targeted against areobic gram-positive bacteria. Oritavancin is also given once daily and also has a unique mechanism of action. The new agent that I’m most familiar with is dalbavancin.29-31 The main advantage of that drug is its extremely long half-life; it can be given just once a week. Therefore, two doses can take care of many types of infections. Dalbavancin is currently undergoing clinical trials for treating skin and skin structure infections.
For these and other new drugs, it will take time and clinical studies to sort out which among them may be the most useful.
Will New Quinolones Emphasize
Gram-Positive Coverage?
Dr. Joseph: I believe there is some work being done on new quinolones that actually have activity against resistant gram positive organisms. So we may have quinolones with anti-MRSA activity.
Dr. Lipsky: The use of quinolones for MRSA is an interesting issue because they were developed in the late 1970s and 1980s when we needed drugs to treat gram negative rods. Aerobic gram-negative organisms were the most feared pathogens back then and the fluoroquinolones were very effective for these infections. They also had the advantage of being able to be given orally. As the need for new antimicrobials switched to ones with a better gram-positive spectrum, new quinolones have also been developed to meet this need. Most of the new quinolones retain much of their gram-negative activity but the prevalence of resistance among Staph aureus and other common gram-positive isolates has increased in the past decade.
I believe the pharmaceutical companies are developing newer fluoroquinolone agents that will be specifically targeted against gram-positive pathogens.
Is Ciprofloxacin Being Overutilized?
Dr. Joseph: Recently, I was sitting on a panel and one of the podiatrists mentioned that at his institution the rate of resistance of staphylococci to levofloxacin was up to about 42 percent. I personally haven’t seen it that high and was amazed when I heard that but I know it’s due to the overuse of ciprofloxacin. I think there has been so much overuse of ciprofloxacin that the resultant cross-resistance is going to be a real issue. I don’t know if anybody else on the panel has seen that in their institutions.
Dr. Lipsky: We’ve seen an increasing incidence of resistance of staphylococcal isolates to ciprofloxacin in our hospital and it’s currently 40 to 50 percent. The incidence of resistance to levofloxacin is in the 20 to 25 percent range but I think it will become greater given the amount of levofloxacin that is currently being used.
Dr. Armstrong: As early as 1994 in Detroit, we identified a significant association between long-term ciprofloxacin use and osteomyelitis caused by methicillin-resistant organisms.32 There have been many other reports of this as well, particularly in recent years.33-37
Drugs In Development: Is There
Too Much Emphasis On IV Therapy?
Dr. Armstrong: When I look at some of the newer products that are either in the pipeline or currently available, they are almost all parenteral drugs. This might be problematic. We also hospitalize fewer patients with infections now and treat many as outpatients. Effective oral antibiotics would be advantageous for this setting.
Dr. Lavery: Linezolid is available orally so certainly that’s one choice. Another option is using IV therapy with a long half-life that can be dosed every seven to 10 days. Certainly, we’ll see these people in the infusion center for their dose and they will be there for two hours and go home. We won’t have as many people with home IV therapy or in skilled nursing facilities for prolonged periods of time because of those kinds of access issues.
Dr. Armstrong: I think maybe oral agents and parenteral drugs with very long half-lives might be a way forward in the future as we try to get these patients out of the hospital and back to living their lives.
Addressing The Rise
Of Community-Acquired MRSA
Dr. Lipsky: You raised the issue of oral therapy and I think it’s important to talk about the fact that there are a number of oral agents that work against community-acquired Staphylococcus aureus infections.
Dr. Armstrong: That’s been the case for a long time.
Dr. Lipsky: While methicillin resistant Staph aureus infection was predominantly a hospital issue for decades, it has now become a community issue. The community-acquired strains tend to be different from the hospital-acquired strains in a number of ways.38 First among these differences are those involving antibiotic susceptibility.
Community acquired MRSA strains are usually sensitive to most other non-beta-lactam agents commonly used as anti-staphylococcal drugs, with the possible exception of erythromycin. Therefore, you can often use such oral agents as tetracyclines, trimethoprim-sulfamethoxazole and clindamycin. In the old days, we sometimes used oral chloramphenicol, but because of bone marrow toxicity, it’s rarely used now.
|  | | Here is a postoperative infection following a first MTPJ arthroplasty in a patient who has neuropathy and diabetes. The culture and sensitivities grew out as community-acquired MRSA.
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Oral rifampin is another good anti-staphylococcal drug, but only when it is combined with another active antibiotic. Some fluoroquinolones can also be used for sensitive MRSA isolates, although there are generally better indications for those drugs.
The community-acquired infections also tend to occur in younger patients who are otherwise healthy as opposed to the hospital-acquired strains that generally infect elderly, chronically ill patients who have received a lot of antimicrobial therapy.
Dr. Joseph: I think most people consider MRSA as some homogenous organism that’s out there. As Dr. Lipsky said, we really have to start differentiating community-acquired (or associated) MRSA from the hospital-acquired MRSA. For example, in the literature, they discuss the use of CA-MRSA versus H-MRSA. With the exception of the microbiological and genetic typing worlds, this is a relatively new concept. However, from a clinical standpoint, I think that people have to really take what Dr. Lipsky said to heart, that we have to look at MRSA as more of a heterogenous group of organisms, that there are different strains of it with different genetic makeup that do have different antibiotic susceptibility patterns. We probably should be looking at the premise of two different organisms as opposed to one.
Dr. Armstrong: Just as in the past when we looked at all Staph aureus as a homogeneous entity, perhaps we should be more clinically vigilant in subcategorizing these resistant organisms based on their source and phenotype. I think that’s a very important point.
Dr. Lipsky: I wanted to add one other point to what Dr. Joseph said. For a while, we wondered if isolating MRSA from an infection was really such a big deal. Was it a more virulent organism or simply a Staph aureus isolate that is less susceptible to semi-synthetic penicillins? Most data suggested that it was mainly an issue of antimicrobial resistance.39-41 MRSA appeared to be no more virulent than methicillin sensitive strains that caused infections in hospitalized patients. Some actually argued that because of the burden of the extra genetic machinery that was necessary to produce resistance to many different types of antibiotics, MRSA was actually a slower growing and less virulent organism than MSSA.
Unfortunately, we have the opposite situation with the community-acquired strains. While they have more restricted antimicrobial resistance, being susceptible to a variety of other antibiotics as we have said, community-acquired MRSA tend to be more virulent strains. They are at least as virulent as methicillin sensitive Staph aureus (MSSA). Some have a variety of toxins, including leucocyte toxins, exfoliative toxins and exotoxins that make them highly virulent pathogens. We’ve seen large outbreaks in the community including several deaths caused by community-acquired MRSA. This may be a more worrisome organism, particularly if it were to pick up some of the genetic machinery allowing it to become resistant to other commonly used antibiotics.
Dr. Joseph: There’s actually an interesting paper by Engemann that actually looked at adverse clinical and economic outcomes attributable to MRSA.42 They didn’t particularly divide it into the community-acquired strains versus the hospital-acquired strains. I think that’s a really fascinating point that Dr. Lipsky brings up with the community-acquired strains, which are more susceptible and may actually be the more dangerous organisms.
Is MRSA really a problem or is it just some slow-growing, almost lazy organism? Patients who are admitted to the hospital with MRSA have a greater 90-day mortality rate than patients infected with MSSA.42 They had a greater duration of hospitalization after infection and they had significantly higher hospital charges, probably because of the longer hospitalization.42 This is not only a problem in that the numbers are increasing, but these organisms, either the community- or hospital- acquired organisms, are in fact causing lots of patient morbidity.
Will Future Treatment Protocols
Address Different Strains Of MRSA?
Dr. Lavery: So are we going to see better information get provided to us by the microbiology laboratory in regard to MRSA strains and perhaps more guidance for treatment approaches based on the strain?
Dr. Lipsky: Some of the papers coming from the microbiology and laboratory world are looking at rapid methods of determining which patients have Staph aureus infections and which of those strains are resistant to methicillin and other antibiotics.
I think we’ll begin to get more rapid information to help us determine whether an infection is caused by MRSA. And if the infections are caused by MRSA, do they appear to have the genetic components that make them look more like community-acquired rather than hospital-acquired strains? We should also see more rapid information about antimicrobial resistance. That will help us narrow the gap between empiric therapy and definitive therapy. |
